Inorganic phosphate is critical to the human body on many levels. At the cellular level it is required as a component of energy metabolism, kinase signaling and in the formation and function of DNA and lipids. Traditionally, inorganic phosphate has been thought of as a passive, required ion for these processes, however, recent data suggests a more active role for this ion in the regulation of cell function. Published and preliminary in vitro results have revealed that exposure of a variety of cell types to elevated inorganic phosphate will alter growth properties, specific signal transduction pathways, and gene expression, including cancer and metastasis related factors such as osteopontin, c-fos, Egr1 and Cox-2. Our preliminary in vivo results corroborate the in vitro studies and suggest that the levels of serum inorganic phosphate alter tumorigenesis in the two-stage model of skin carcinogenesis. Taken together the results suggest that the level of available inorganic phosphate may be an important predisposing risk factor to the growth and transformation potential of cells. The main source of serum inorganic phosphate is from dietary intake and due, in part, to the increased consumption of processed foods, the amount of inorganic phosphate in the American diet continues to rise above levels already considered high by the FDA. Although it is becoming increasingly apparent that diet can have profound effects on functional genomics, however, to date the molecular and cellular responses to changes in serum phosphate levels have only begun to be investigated. This proposal will test the hypothesis that; the amount of available inorganic phosphate alters the growth and transformation potential of cells through specific cellular and molecular regulatory signals. To test the hypothesis we will utilize defined in vitro cell culture models of transformation for mechanistic studies in combination with the established two-stage model of skin carcinogenesis to determine physiological relevance. The studies propose herein will: 1) Determine the cellular and molecular mechanisms of inorganic phosphate regulated proliferation and transformation: This line of investigation will test the hypothesis that phosphate transport in combination with FGF receptor activation regulates the small GTP binding protein, N-ras and subsequent AP-1 transcriptional activation necessary for the phosphate-induced proliferation and transformation response. 2) Define the role of dietary inorganic phosphate on proliferation, transformation and tumorigenesis in vivo: This aim will test the hypothesis that reducing dietary inorganic phosphate consumption will decrease tumorigenesis in the DMBA/TPA two-stage skin carcinogenesis model. PUBLIC HEALTH RELEVANCE: Inorganic phosphate is a common dietary element and the amount in the American diet continues to rise above levels already considered high by the FDA. Inorganic phosphate has recently been demonstrated to alter gene expression and the growth phenotype of a variety of cell types however, there is little research regarding the affects of dietary phosphate intake on human health. This proposal will investigate the role of dietary inorganic phosphate in cancer initiation, promotion and progression.